Endothelial cell differentiation is essential for blood vessel development and function in both normal and disease settings. For example, in the developing embryo differentiation of arterial and venous endothelial cells is essential for proper vessel patterning and circulatory function. In some cases of congenital vascular disease, endothelial differentiation is perturbed leading to vascular malformations. In other cases, it would be beneficial to actively program blood vessel identify by modulating endothelial differentiation. Thus, a better understanding of the molecular basis of normal endothelial differentiation is highly relevant. While transcriptional hierarchies responsible for cellular differentiation have been extensively characterized in other tissues, much less is known about such programs in endothelial cells. Since the signals that govern pathological neovascularization are also used in the embryo during normal blood vessel development and these signals are evolutionarily conserved, it is possible to study this process using model systems. In this proposal, we will take advantage of the many benefits of the zebra fish as a model system to define the role of the Ets transcription factor, etv2 during endothelial specification. We will investigate the mechanisms responsible for Etv2 regulation at both the post-translational and transcriptional levels. We will also identify direct targets of etv2 relevant to endothelial specification, with a particular emphasis on genes encoding transcription factors. We will subsequently identify regulatory gene programs initiated by etv2 and downstream transcription factors and determine how these contribute to endothelial differentiation. Finally, we will determine the role of other Ets transcription factors in transducing external signals to drive artery gene expression and morphogenesis.